Insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations. In insulin resistance, the body secretes abnormally high amounts of insulin to compensate for this defect; failing which, the plasma glucose concentration inevitably rises and develops into diabetes. Among the developed countries, diabetes mellitus is a common problem and is associated with a variety of abnormalities including obesity, hypertension, hyperlipidemia (J. Clin. Invest., (1985) 75:809-817; N. Engl. J. Med. (1987) 317: 350-357; J. Clin. Endocrinol. Metab., (1988) 66:580-583; J. Clin. Invest., (1975) 68:957-969) and other renal complications (See Patent Application No. WO 95/21608). It is now increasingly being recognized that insulin resistance and relative hyperinsulinemia have a contributory role in obesity, hypertension, atherosclerosis and type 2 diabetes mellitus. The association of insulin resistance with obesity, hypertension and angina has been described as a syndrome having insulin resistance as the central pathogenic link-Syndrome-X. In addition, polycystic ovarian syndrome (Patent Application No. WO 95/07697), psoriasis (Patent Application No. WO 95/35108), dementia (Behavioral Brain Research (1996) 75:1-11) etc. may also have insulin resistance as a central pathogenic feature.
A number of molecular defects have been associated with insulin resistance. These include reduced expression of insulin receptors on the plasma membrane of insulin responsive cells and alterations in the signal transduction pathways that become activated after insulin binds to its receptor including glucose transport and glycogen synthesis.
Since defective insulin action is thought to be more important than failure of insulin secretion in the development of non-insulin dependent diabetes mellitus and other related complications, this raises doubts about the intrinsic suitability of antidiabetic treatment that is based entirely upon stimulation of insulin release. Recently, Takeda has developed a new class of compounds which are the derivatives of 5-(4-alkoxybenzyl)-2,4-thiazolidinediones of the formula (II) (Ref. Chem. Pharm. Bull. 1982, 30, 3580-3600). In the formula (II), V represents substituted or unsubstituted divalent aromatic group and U represents various groups which have been reported in various patent documents. ##STR3##
By way of examples, U may represent the following groups:
(i) a group of the formula (IIa) where R.sup.1 is hydrogen or hydrocarbon residue or heterocyclic residue which may each be substituted, R.sup.2 is hydrogen or a lower alkyl which may be substituted by hydroxy group, X is an oxygen or sulphur atom, Z is a hydroxylated methylene or a carbonyl, m is 0 or 1, n is an integer of 1-3. PA1 vi) a group of formula (II 1), where R is (C.sub.1 -C.sub.6) alkyl groups, cycloalkyl group, furyl, thienyl, substituted or unsubstituted phenyl group, X is hydrogen, methyl, methoxy, chloro or fluoro. PA1 reacting the compound of general formula (III), where G is a CHO group with 2,4-thiazolidinedione or 2,4-oxazolidinedione to yield a compound of general formula (XII) ##STR29## where A, B, D, X, Ar, k, p and Z are as defined earlier and removing the water formed during the reaction by conventional methods.
These compounds have been disclosed in the European Patent Application No. 0 177 353 ##STR4##
An example of these compounds is shown in formula (IIb) ##STR5## (ii) a group of the formula (IIc) wherein R.sup.1 and R.sup.2 are the same or different and each represents hydrogen or C.sub.1 -C.sub.5 alkyl, R.sup.3 represents hydrogen, acyl group, a (C.sub.1 -C.sub.6) alkoxycarbonyl group or aralkyloxycarbonyl group, R.sup.4 -R.sup.5 are same or different and each represent hydrogen, C.sub.1 -C.sub.5 alkyl or C.sub.1 -C.sub.5 alkoxy or R.sup.4, R.sup.5 together represent C.sub.1 -C.sub.4 alkenedioxy group, n is 1, 2, or 3, W represents CH.sub.2, CO, CHOR.sup.6 group in which R.sup.6 represents any one of the items or groups defined for R.sup.3 and may be the same or different from R.sup.3. These compounds are disclosed in the European Patent Application No. 0 139 421. ##STR6##
An example of these compounds is shown in (IId) ##STR7## iii) A group of formula (IIe) where A.sup.1 represents substituted or unsubstituted aromatic heterocyclic group, R.sup.1 represents a hydrogen atom, alkyl group, acyl group, an aralkyl group wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group, n represents an integer in the range from 2 to 6. These compounds are disclosed in European Patent No. 0 306 228. ##STR8##
An example of this compound is shown in formula (IIf) ##STR9## iv) A group of formula (IIg) where Y represents N or CR.sup.5, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 represents hydrogen, halogen, alkyl and the like and R.sup.6 represents hydrogen, alkyl, aryl and the like, n represents an integer of 0 to 3. These compounds are disclosed in European Patent Application No. 0 604 983. ##STR10##
An example of this compound is shown in formula (IIh) ##STR11## v) A group of formula (IIi a-d) where R.sup.1 represents hydrogen atom, halogen, linear or branched (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, trifluoromethyl or cyano groups and X represents S, O or NR where R.dbd.H or (C.sub.1 -C.sub.6)alkyl group. These compounds are disclosed in European Patent Application No. 0 528 734. ##STR12##
An example of this class of compound is shown in formula (IIj) ##STR13##
Still another class of antihyperglycemic agents are 5-substituted oxazolidine-2,4-diones and 2-substituted-1,2,4-oxadiazolidine-3,5-diones which can be represented in the formula (IIk), ##STR14## where V represents substituted or unsubstituted divalent aryl or hetero aryl group, W represents various groups which have been reported in various patent documents, A represents nitrogen atom or a CH group and B is an oxygen atom.
By way of examples, W may represent the following groups:
These compounds have been disclosed in the U.S. Pat. No. 5 037 842. ##STR15##
An example of these compounds is shown in formula (IIm). ##STR16## (vii) A group of formula (IIn) wherein A.sup.1 represents a substituted or unsubstituted aromatic heterocyclyl group; R.sup.1 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted or a substituted or unsubstituted aryl group, n represents an integer in the range of from 2 to 6. These compounds have been disclosed in the patent application No. WO 92/02520. ##STR17##
An example of these compounds is shown in formula (IIo). ##STR18## (viii) A group of formulae (IIp) and (IIq), where R.sup.1 is hydrogen, (C.sub.1 -C.sub.8)alkyl, (C.sub.1 -C.sub.8)alkoxy, trifluoroalkoxy, halogen or trifluoromethyl group, R.sup.2 is hydrogen or methyl and X is oxygen or sulfur. These compounds have been described in U.S. Pat. No. 5 480 486. ##STR19##
An example of these compounds is shown in formula (IIr) ##STR20##